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1 Division of Developmental Genetics, National Institute of Genetics, Mishima, Shizuoka, 411-8540, Japan
2 Department of Microbiology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
3 Department of Genetics, SOKENDAI, Mishima, Shizuoka, 411-8540, Japan
4 CREST, JST, Saitama, 332-0012, Japan
5 Division of Morphology and Organogenesis, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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A good system to probe the in vivo function of negative regulators of the Ras/MAPK signaling pathway is the Drosophila compound eye, where Ras signal directs neuronal specification (Wolff & Ready 1993; Freeman 1996). The compound eye consists of a stereotyped array of 800 ommatidia, or unit eyes, each of which comprises an invariant set of 20 cells including eight photoreceptor neurons, called R1 through to R8 cells (Wolff & Ready 1993). Photoreceptor neurons are classified into two categories according to their positions in the ommatidium. The R7 and R8 cells that are located at the center of the ommatidium are called ‘inner photoreceptor neurons,’ while the R1–R6 cells that surround the R7 and R8 cells are called ‘outer photoreceptor neurons’ (Tomlinson & Ready 1987). In the eye imaginal disc, undifferentiated cells are induced to assume the photoreceptor neuronal fate by the TGF-
homolog Spitz-EGF (Freeman 1994a; Tio & Moses 1997). Spitz-EGF is received by the EGF receptor (EGFR), which in turn activates Ras/MAPK signaling, leading to neuronal differentiation (Freeman 1996). While there are a large number of cells that are competent to be induced, the outcome of induction is remarkably constant; each ommatidium invariably contains eight photoreceptor neurons. To achieve such a high level of precision, induction must be controlled by both positive and negative regulators that adjust the level of the inductive signaling.
A characteristic aspect of neuronal induction during ommatidial assembly is that the photoreceptor neurons are recruited in a stereotyped sequence (Tomlinson & Ready 1987). In the third instar larval eye imaginal disc, a moving front of differentiation called the morphogenetic furrow sweeps across the disc from posterior to anterior, generating an equally spaced array of founder cells, the R8 neurons. Following R8 specification, the R1 through to R7 cells are sequentially induced through activation of Ras/MAPK signaling pathway (Wolff & Ready 1993; Freeman 1996; Kumar et al. 1998). For instance, R8 cells secrete Spitz-EGF to induce neighboring undifferentiated cells to become R2 and R5 cells (Tomlinson & Ready 1987; Freeman et al. 1992a). Subsequently, R2/R5 cells also behave as ‘inducing cells’ by secreting Spitz-EGF, thereby recruiting R3/R4 and then R1/R6 cells from the pool of undifferentiated cells (Tomlinson & Ready 1987; Tomlinson et al. 1988). Finally, an inductive signal emitted from the R8 cell triggers activation of Ras signaling in the presumptive R7 cell (reviewed in Zipursky & Rubin 1994). Neither R7 nor R3/R4/R1/R6 cells act as a source of Spitz-EGF themselves. Thus outer photoreceptor neurons can be classified into two groups: R2/R5 cells, which possess inducing ability, and R3/R4/R1/R6 cells, which themselves do not induce other cells. These two groups can be distinguished by the expression of a nuclear receptor Seven-up (SVP), the Drosophila homolog of the transcription repressor COUP-TF (Wang et al. 1989; Mlodzik et al. 1990; Kliewer et al. 1992; Tran et al. 1992; Fjose et al. 1993). It is not known whether such molecular heterogeneity exerts any control on the spatio-temporal characteristics of the activation of Ras/MAPK signaling and the stereotyped induction process.
SPRY and AOS are two well known negative regulators of this pathway (Perrimon & McMahon 1999; Freeman 2000). SPRY binds several intracellular signaling components of the Ras/MAPK signaling pathway and blocks signals downstream of EGF receptor (EGFR) activation, whereas AOS is a secreted protein that binds Spitz-EGF and thereby sequesters this ligand from EGFR on the cell surface (Schweitzer et al. 1995; Casci et al. 1999; Jin et al. 2000; Yusoff et al. 2002; Hanafusa et al. 2002; Klein et al. 2004). Loss of spry or aos function causes production of extra photoreceptor neurons, which originate from two types of non-neuronal cells within the ommatidium: lens-secreting cone cells and mystery cells transiently associated with the ommatidial precluster (Wolff & Ready 1993). This suggests that the role of these negative regulators is to prevent excessive neuronal induction from cells that normally do not become neurons (Freeman et al. 1992b; Sawamoto et al. 1996; Casci et al. 1999; Kramer et al. 1999). However, these negative regulators are both induced by the Ras signal which are active in presumptive neurons, and are in fact also expressed in photoreceptor neurons (Golembo et al. 1996; Hacohen et al. 1998; Casci et al. 1999; Kramer et al. 1999). spry, for example, is strongly expressed in a subset of photoreceptor neurons at much higher levels than in the non-neuronal cells that exhibit a phenotype in spry mutant ommatidia (Casci et al. 1999; Kramer et al. 1999). This suggests that spry may have an additional role in presumptive neurons during their sequential induction. Furthermore, spry and aos have different spatio-temporal expression patterns (Freeman et al. 1992b; Okano et al. 1992; Kramer et al. 1999), suggesting that their transcriptional regulation involves cell-type specific transcription factors.
This study employs a genetic approach in order to further elucidate the role of SPRY and AOS in fine-tuning signaling activity during these inductive events. We report that the interplay between these negative feedback loops is required for the cell-type specific expression of these negative regulators between the two groups of outer photoreceptor neurons to control proper responsiveness to the inductive signal. When this system fails, as in spry mutants, a constant outcome of sequential induction can no longer be maintained. We propose that SPRY-mediated inhibition of AOS expression in inducing cells avoids competitive interaction with an inductive signal of Spitz-EGF ligand, while the AOS-mediated extracellular feedback loop in the induced neurons serves to terminate the inductive sequence by inactivating Spitz-EGF. It is likely that cell-type specific utilization of distinct negative feedback loops is a general mechanism that contributes to precise pattern formation within the multicellular field.
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Results |
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In the compound eyes of normal animals, the induction process is remarkably constant in its outcome; each ommatidium always contains six outer photoreceptor neurons (R1–R6) and two inner photoreceptor neurons, R7 and R8 (Wolff & Ready 1993). The major phenotype reported for spry loss of function mutants is an excess number of photoreceptor neurons (Casci et al. 1999; Kramer et al. 1999). Interestingly, however, some ommatidia exhibited the opposite phenotype: fewer number of outer photoreceptor neurons per ommatidia (Fig. 1; Kramer et al. 1999). The average number of the outer photoreceptor neurons in spry mutant was almost identical to the number in normal animals (Fig. 1). Nonetheless, spry mutant could not maintain the constancy in the number of outer photoreceptor neurons, generating the standard deviation of 1.05 (Fig. 1). An excess in the number of outer photoreceptor neurons has previously been explained by a cell-autonomous function of spry that prevents neuronal induction in non-neuronal cells (Casci et al. 1999; Kramer et al. 1999). This, however, cannot adequately account for the reduction in the number of outer photoreceptor neurons. To address the mechanisms for this reduction phenotype of spry, we investigated the functions of spry in neurons and its possible interactions with other negative regulators in the Ras/MAPK pathway.
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It has previously been shown that the expression of spry and aos depends on activity of the Ras/MAPK signaling pathway (Golembo et al. 1996; Casci et al. 1999; Kramer et al. 1999). This suggests that loss of the spry-mediated negative feedback loop may result in hyperactivation of Ras/MAPK signaling, which in turn enhances the expression of the aos gene. Here we reexamine the expression of spry and aos in greater depth in order to identify any possible interactions between these regulators. We used enhancer trap lines spry9143 and aossty2, which are expressed in the same spatio-temporal patterns as endogenous spry and aos (Freeman et al. 1992b; Okano et al. 1992; Kramer et al. 1999).
spry and aos are first expressed in presumptive photoreceptor neurons just posterior to the morphogenetic furrow. Initially, all photoreceptor neurons express both spry and aos. However, by the sixth ommatidial column posterior to the morphogenetic furrow, this uniform expression changes dramatically such that spry becomes confined to the R2/R5/R7 cells (Fig. 2B,D) and aos to the R3/R4/R1/R6/R7 cells (Fig. 2C,D). We hypothesized that this complementary pattern of expression in R1–R6 outer photoreceptor neurons is generated by an interaction between the two molecules, and that this has important consequences in fine-tuning the activity of the Ras/MAPK pathway in photoreceptor neurons. To explore this possibility, we initially investigated the expression of each of these negative regulators in the reciprocal mutant background. We found that a loss of aos function had no significant effect on the expression pattern of spry (Fig. 3B). In contrast, a loss of spry function dramatically altered the expression pattern of aos; in these animals, aos expression did not become confined to the R3/R4/R1/R6 cells but continued to be expressed in R2/R5 cells as well (Fig. 3J). These results strongly suggest that spry function acts to repress aos expression in R2/R5 cells. To test this possibility, we ectopically expressed spry in R3/R4/R1/R6 cells, using the sevenless (sev) enhancer (sevE-spry), and observed a down-regulation of aos expression in these cells (Fig. 3K). Taken together, these results show that spry generates the dynamic pattern of aos expression, through repression its in R2/R5 cells.
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Because Ras/MAPK signaling is required for the differentiation of all photoreceptor neurons (Freeman 1996) and spry transcription is induced by the activity of the Ras/MAPK signaling pathway (Casci et al. 1999; Kramer et al. 1999), it is difficult to explain the subsequent restriction of spry expression to the R2/R5 cells. One possible scenario to explain this expression pattern is that R3/R4/R1/R6 cells express a transcriptional repressor of spry. A good candidate for this is SVP, which is normally expressed in R3/R4/R1/R6 cells of the developing ommatidia (Mlodzik et al. 1990). To investigate if svp is able to repress spry expression, we ectopically expressed svp in R2/R5 cells using the rough (ro) enhancer (roE-svp) (Kramer et al. 1995) and found that spry expression in these cells was reduced below the level seen in R3/R4/R1/R6 cells (Fig. 3C). Conversly, loss of svp function resulted in an increase in spry expression in R3/R4/R1/R6 cells up to the level normally seen in the R2/R5 cells (Fig. 3A,D). This effect of svp on spry expression could be due either to a direct effect on spry expression, or to an indirect effect through cell fate transformations toward R7, a cell with high spry expression level (Mlodzik et al. 1990). To distinguish between these two possibilities, we ectopically expressed svp in R7 cells under the control of the sev enhancer (sevE-svp), a condition which is known not to have any effect on the cell fate of R7 cells (Hiromi et al. 1993). Under this manipulation, ectopic expression of svp repressed the high levels of spry in R7 cells (Fig. 3G,H), indicating that svp can suppress spry expression independent of cell fate change. This result suggests that the higher level of spry expression seen in R3/R4/R1/R6 cells of svp mutants is not a consequence of them being transformed into R7 cells. Thus a complementary expression pattern of svp and spry in photoreceptor neurons is established, at least in part, through the svp-mediated repression of spry in R3/R4/R1/R6 cells.
Another possible explanation for the R2/R5 specific expression of spry is that expression is maintained by a transcriptional activator in these cells. Rough (RO), a homeodomain-containing protein known to positively regulate the transcription of downstream target genes (Kimmel et al. 1990; Freeman et al. 1992a) is expressed in R2/R5 cells and is required for specifying R2/R5 identity (Tomlinson & Ready 1987). We examined spry expression in a ro mutant background and found that its expression in R2/R5 cells is reduced to the level of expression in R3/R4/R1/R6 cells (Fig. 3E). This is suggestive that ro is necessary for the higher expression of spry in R2/R5 cells. However, it has previously been reported that the loss of ro function causes ectopic expression of svp in R2/R5 cells, resulting in the transformation of these cells to R3/R4 cells (Heberlein et al. 1991). To test whether loss of ro function causes this reduction in spry expression through ectopic expression of svp in R2/R5 cells, we examined spry expression in a ro and svp double mutant background. The expression of spry in the double mutants closely resembled that observed in the svp single mutant (Fig. 3D,F), indicating that svp is epistatic to ro in the regulation of spry expression. This suggests that rather than directly activating or maintaining spry expression in R2/R5 cells, ro indirectly up-regulates spry expression through the repression of svp in these cells. Taken together, we conclude that R2/R5 specific expression of spry is established through its repression in R3/R4/R1/R6 cells by svp.
svp is necessary for proper neuronal induction
The regulation of negative regulators of Ras signaling by svp also accounts for certain aspects of the svp mutant phenotype that has so far remained unexplained. In addition to the cell-autonomous transformation of outer photoreceptor neurons that normally express svp towards R7 cells, svp mutant ommatidia have a non-cell autonomous phenotype, i.e. generation of supernumerary outer photoreceptor neurons (Mlodzik et al. 1990). The non-cell autonomous nature suggests that this phenotype is mediated by a secreted factor, such as AOS. To test this, we examined aos expression in svp mutants. Loss of svp function resulted in lower levels of aos expression in R3/R4/R1/R6 cells (Fig. 3L), whereas the ectopic expression of svp, under the control of the ro enhancer (roE-svp), resulted in higher levels of aos expression in R2/R5 cells (Fig. 3M). These results indicate that svp expression in R3/R4/R1/R6 cells is necessary for the higher levels of AOS, which, in turn, prevents the induction of excess photoreceptor neurons.
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Discussion |
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When this cell-type specific regulation is lost, the system can no longer maintain the precision that normally achieves invariant number of ommatidial components. For example, in the case of spry mutants, ectopic and high levels of AOS expression continues in the R2/R5 cells (Fig. 4D), which, in turn, likely causes a reduction in outer photoreceptor neurons in the vicinity of R2/R5 cells, as has been observed upon over-expression of aos (Freeman 1994b; Sawamoto et al. 1994). On the other hand, loss of spry also causes excess photoreceptor neurons through transformation of non-neuronal cells to a neuronal fate (Fig. 4E; Casci et al. 1999; Kramer et al. 1999). As a result of the concomitant reduction and overproduction of neurons, the constancy of the neuronal cell number is lost (Fig. 1). A similar mechanism may underlie the variation in the neuronal number associated with the loss of function of svp (Mlodzik et al. 1990).
Presently, one widely accepted proposal is that the presence of multiple negative feedback loops constitutes a guarantee system that delivers ‘developmental robustness’ through functional redundancy (Fig. 4A). However, as the induction of these negative regulators (i.e. SPRY, AOS) depends on the activation of their pathway (i.e. Ras/MAPK), each feedback loop is capable of influencing the expression of other negative feedback loops. Therefore, rather than thinking of these feedback loops as merely functioning simultaneously and possibly redundantly, it may be more informative to view these interactions as a network (Fig. 4B). For instance, a negative regulator of Decapentaplegic (DPP) signaling in Drosophila, called Daughter against DPP (DAD), which is a distantly related member of the SMAD family (Tsuneizumi et al. 1997), and a putative nuclear transcriptional repressor Brinker (BRK) (Campbell & Tomlinson 1999; Jazwinska et al. 1999) are both expressed in a signal-dependent manner through the actions of negative feedback loops (reviewed in Perrimon & McMahon 1999). Interestingly, brk is expressed at low or intermediate levels of the DPP signaling, complementary to regions of high DPP signaling that activate the DAD-mediated negative feedback loop. Although the functional relationship between DAD and BRK is still unclear, this suggests that cell-type specific utilization of these negative regulators could be necessary to control downstream target genes for each distinct cell-type.
In conclusion, the significance of multiple negative feedback loops within the Ras/MAPK signaling pathway was analyzed by genetic approach using the Drosophila compound eye. We describe that the cell-type specific expression of these negative regulators is controlled by interplay between the negative regulators and cell-intrinsic factors and that this is required for a constant outcome of neural induction. Our findings show that the presence and cell-type specific utilization of multiple negative feedback loops allow a strict spatiotemporal regulation of signaling, which delivers ‘developmental robustness’ as well as contributes to a constant outcome in pattern formation.
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Experimental procedures |
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The following fly lines were used for analysis in mutant backgrounds: rox63, aos257, spry
5, svpe22 for each null allele, and gene expression was followed by using aossty2 (aos-lacZ) and spry9143 (spry-lacZ) enhancer trap lines (for details on mutants used, see Flybase; http://flybase.bio.indiana.edu). Ectopic expression of the svp gene was followed using sev-svp1, sev-svp2, ro-svp1 and ro-svp2 constructs (Hiromi et al. 1993; Kramer et al. 1995). As previously reported (Hiromi et al. 1993), svp2 construct had a stronger effect than svp1 construct, and this was consistent in all our experiments. All figures show the experiments in svp1 construct except Fig. 3H showing svp2. UAS-spry (Hacohen et al. 1998) was placed under sevE-GAL4 K25 (Brunner et al. 1994) for ectopic expression of spry gene.
An eye-specific mosaic clone of svp was generated by using the FRT technique in a Minute (M) mutant background (Xu & Rubin 1993): w1118; FRT 82B, svpe22/TM6B females were crossed with yw, eyelessFLP; FRT82B, P[ub-GFP], M (96C)/TM6B males. Tb+ female larvae were collected for the dissection. This system works efficiently in the larval eye-antennal disc (Newsome et al. 2000; about > 90% area occupied by the mutant clone in chromosome 3R).
Immunohistochemistry
Eye discs were prepared (described in Tomlinson & Ready 1987) and stained with 0.5 mg/mL DAB or examined by confocal microscopy. Primary antibodies were: mouse anti-ELAV (1 : 2, Developmental Studies Hybridoma Bank, University of Iowa, USA), mouse anti-ß-galactosidase (1 : 100; Promega). Secondary antibodies were: HRP-conjugated goat anti-mouse, Cy3-anti-mouse, FITC-anti-rabbit (1 : 100, Jackson Laboratories). Biotinyl Tyramide (from the TSA-indirect amplification kit, NEN) was used for signal amplification. We stained 4–5 mutant discs along with the same number of control discs in the same Eppendorf tube. At least 3 independent experiments were performed for each genotype. Photographs were taken at the same magnification, light power, aperture and exposure time. In every case, the control animals were in a yellow background and the mutant animals were not, so that we were able to determine the genotype of each eye-disc according to the color of its attached mouth hook.
Histology
Plastic sections of the adult eye were generated by first fixing the adult head in 2% glutaraldehyde in 0.1 M phosphate buffer (pH 7.2) overnight at 4 degrees. After washing in 0.1 M phosphate buffer, the tissue was postfixed in 1% OsO4 in the same buffer for 2 h at room temperature, then dehydrated in a graded ethanol series. After cleaning in propylene oxide, the tissue was embedded in resin (Fluka), sectioned and stained with toluidine blue.
Figure preparation
Figures were prepared according to ‘Barrier-free presentation that is friendly to colorblind people’ (http://jfly.iam.u-tokyo.ac.jp/color).
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: maokabe{at}jikei.ac.jp
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References |
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Received: 8 March 2005
Accepted: 10 April 2005
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